PTC Therapeutics, Inc. (PTCT) Earnings Call Transcript & Summary

Good morning or good afternoon, I guess, and thank you, everyone, for joining the virtual UBS Global Healthcare Conference. I'm Colin Bristow. I'm one of the biotech analyst here at UBS. It's my pleasure to have PTC Therapeutics here with us today. Speaking on behalf of the company, we have Matt Klein, Chief Development Officer; Eric Pauwels, Chief Business Officer; and Kylie O'Keefe, SVP, Head of Global Commercial and Corporate Strategy. So thank you all for joining us today. Before we start, if anyone has a question, there is a question functionality in this global meet system. But alternatively, feel free to e-mail me at [email protected], and I can field the question for you. So with that, I'll hand it over to Matt. Matt, over to you. Thanks.

Thank you, Colin. Let me start with a brief introduction to PTC. For those of you who don't know PTC, we are global commercial diversified biopharmaceutical company focused on discovering, developing and commercializing innovative therapies to treat rare disorders. As recently discussed in our Q1 earnings call, we are excited with the progress we've made on all fronts, from discovery to development and commercialization. Despite all the challenges of the pandemic, which we've been managing for over a year, we were able to adapt quickly, progress our pipeline and achieve many key value creating milestones. I'll start on the commercial side. The DMD franchise continues to see robust growth. We had one of our strongest quarters ever in commercial revenue. Translarna and Emflaza saw substantial 32% growth in revenues compared to the first quarter of 2020. In addition, Evrysdi, which was developed from our splicing platform, has continued to see strong uptake in the United States. In addition, Evrysdi received EMA approval at the end of March, with the first EU sale the following day, which triggered a $20 million milestone from our partner, Roche. On the R&D side, over the past year, we initiated 5 clinical trials, 3 of which are registration directed. Of the 3 registration-directed trials, 2 are from our Bio-e platform with our small molecule vatiquinone, one mitochondrial epilepsy and one in Friedreich ataxia. These studies are progressing well, and we look forward to sharing updates over the course of the trial. From our splicing platform, following on the heels of the approval and successful launch of Evrysdi, we initiated our Phase I healthy volunteer trial for PTC518 for our Huntington disease program. And we shared the exciting preliminary data from this trial in our recent Huntington's deep dive, including the desired dose-dependent reduction in Huntington mRNA. As we discussed in our earnings call, we plan to share more results as they become available. Looking forward to the remainder of 2021, we've had several upcoming milestones that we're excited about, including the EU CHMP opinion for AADC gene therapy, which would be the first ever approved direct administered gene therapy into the brain. We are planning to initiate the Phase III trial with PTC923 in patients with PKU, where despite available therapies, there remains a large unmet medical need. We'll also continue to have data readouts from the Phase I healthy volunteer study for PTC518 as I mentioned previously, and we will share results from the healthy volunteer study of PTC857, the second molecule from our Bio-e platform being developed for adult neurodegenerative diseases as well as readouts from our early-stage oncology studies. So a lot to look forward to this year, and we look forward to keeping everyone updated on our progress. Colin?

Great. Thanks. So maybe let's start with 518. It's clearly been a source of investor focus and something we spend a lot of time on. Can you just give us the overview of what you've given us so far? And then what we should expect in the near-term around the update on that program?

Yes. Sure. So as I mentioned briefly in my introductory comments, PTC518 is being developed from our splicing platform, and it's really following on the heels of the successful development of Evrysdi, which was the first ever small molecule splicing compound recently approved for spinal muscular atrophy. So from the SMA program, we really were able to develop a blueprint for preclinical as well as clinical development of a splicing molecule, small molecule, splicing molecule. Key to this molecule is the fact that it's orally administrated titratable and importantly, has broad brain biodistribution. What we've been able to show in our preclinical work is that it gets to every region of the brain, which is incredibly important given the fact, of course, that Huntington disease is a total brain disorder. And so to have an effective therapy, you really need to be able to be effective in every area of the brain that contributes to the disease pathology. As we moved PTC518 through it's preclinical stages, it was optimized for selectivity, specificity, penetration of the blood-brain barrier and lack of efflux. That is once it gets across the blood-brain barrier, it stays in, which is really key to its broad brain biodistribution. As we then moved it into Phase I healthy volunteers, we took advantage of the fact that we're able to see a 1:1 ratio between effect on Huntington mRNA production in peripheral blood cells one-to-one with neurons in the brain. That is -- we actually can get a window into the splicing activity in the brain by looking in the blood cells, peripherally, which is a really novel concept. It was something we did in the SMA program and is incredibly important in a healthy volunteer study because we're uniquely able to gather key evidence of splicing activity and mechanism of action confirmation. And so we moved into Phase I, completed 5 dosing cohorts in healthy volunteers in a single ascending dose. We've ended 2 cohorts in multiple ascending dose and demonstrated what we set out to have is the key objective of that Phase I study. That is demonstrating dose-dependent Huntington mRNA reduction. We saw it in the SAD, and then we saw in the first 2 cohorts of the MAD. And importantly, we were able to achieve a reduction of 50% of Huntington mRNA in our lowest MAD dose, which is great because having oral titrable molecule, knowing that we're in our target zone at a very low dose, gives us confidence that we can have room to go higher if need be or even lower if we need be as we move the compound forward. Importantly as well, there was predictable pharmacology in all those cohorts, and there were no drug effects -- safety drug effects identified or reported. So well tolerated, dose-dependent reduction and now we're in the process of finishing up the last key parts of that study. One is what we've called our CSF dosing cohort, where we're going to demonstrate the pharmacology of the drug by looking at CSF levels. And that's going to be very important in terms of confirming that blood-brain barrier penetration a lot reflux and also a food effect study, which will be just an important sort of check box one often does in the Phase I study. And finally, we plan to be reporting out as well protein reduction data because we've shown the mRNA reduction. And as we've seen preclinically and what's well understood in terms of the kinetics of mRNA approaching, we expect them to correlate 1:1. But of course, we look forward to sharing those data once available.

When should we expect that? Sorry, I think it was an echo. When should we expect those data? And how confident are you that it's going to be a 1:1 relationship between the RNA knockdown and the protein?

Yes. So as we mentioned at earnings on the deep dive, we plan to have those studies, the remaining cohorts, dose 7 and that -- those studies completed by the end of Q2, and we'll share the data as soon as they are available from those studies. As I also mentioned, we fully expect that there to be a 1:1 ratio of mRNA to protein reduction. That's what we've seen preclinically. And again, given the stoichiometric relationship that mRNA goes to protein 1:1, we've -- it makes biological sense that what we saw preclinically, the 1:1 ratio will hold up in patients.

Okay. Great. And of course, the other big thing in the Huntington space is obviously the tominersen discontinuation. And now we've seen -- look behind the curtain, we've seen the data of CHDI. What's your view on what was presented? And just -- can you just highlight the differences between your compound and tominersen [indiscernible] tominersen and just again, why you have confidence that you're not going to run into the same issues?

Yes. So if we go back -- let's go back 2 months ago before 3 months ago when there was a great deal of enthusiasm for the approach of HTT [ lowering ]. Very rational and reasonable enthusiasm, given the fact that we're in a unique situation where we could actually target a neurodegenerative disease at its source. Huntington disease results from the production of a toxic Huntington protein, it's toxic to cells, cells get injured, cells die and neurodegeneration ensues throughout the brain. Typically, in neurodegenerative disease, we're usually targeting something way downstream with biochemically or even a late biological effective disease. And here, we have that unique situation where you have monogenetic disease and the ability to intercept ahead of that entire cascade of events that leads to neurodegeneration. So very excited. As well, the accumulation of preclinical and some clinical data showing that by reducing mutant Huntington protein, you can bring benefit or delay onset of Huntington disease. And at the same time, accumulating data showing that you can lower wild-type Huntington certainly to the levels of 50%, 60% in preclinical studies, even up to 70% without ill effect in adult. So that's why there was so much enthusiasm. For us, that enthusiasm hasn't changed. And the reason for that is because when we look at the tominersen data, I think it's quite clear that the data are all consistent with a toxic ASO effect. The ASO modality hypothesis has been well known. I mean it's even -- in SPINRAZA you see evidence of ASO-related toxicity, just at a much lower level, of course, because you're at much lower levels of administered ASO. But if you look at all of the data, it all points in that direction. It can all be -- the hydrocephalus can certainly be explained by the ASO toxicity effect. In fact, when you look, you see an increase in ventricular volume in the patients treated with no change in cortical or striatal volume. That's very important. If that -- if the UHDRS changes and the hydrocephalus were due to a wild-type Huntington reduction, you would expect to see a reduction in the volume of the striatum and the cortex because the way you would have that decrease in function or advancement or progression of disease is from cell toxicity and cell death, and that would present itself with a reduction in the volume of the brain tissue. You're not seeing that. You're seeing isolated significant increase in ventricular volume, which is absolutely consistent with an ASO modality related event. Furthermore, if you look back to the open-label extension in the Phase I/II study, where there was a 4-week dose group and you look at the data from the 4 week dose group, you see large amounts of white blood cells and protein in the CSF. White blood cells and proteins do not belong in the CSF. They should never be there when they're there, it's a bad thing. And what those are there reflecting an immuno-inflammatory response to the administered ASO. Now of course, that 4-week dose group was dropped in favor of 8 and 16-week dose group. But I think what we're seeing at an 8-week time period is the hydrocephalus. You're seeing a reduction -- a worsening in UHDRS scores in that group, not surprising, just given a huge inflammatory stimulus to an already injured brain and you can absolutely expect worsening function. So all in all, when we look at it together, we say all the data point in the direction of the ASO modality hypothesis. We don't see what you would see if it was an HTT-related phenomenon. And so when we have an orally-administered small molecule like 518 that broadly distributes to the brain, that value proposition that we were all excited about 2, 3 months ago remains.

That makes a lot of sense. The -- on the ventricular volume, is the -- have you ever seen a signal for that? Obviously, not in your human studies because I'm sure you've kind of explained, but in nonhuman primates, anything that you dosed up at a higher dose?

We have not seen any ventricular regulator hydrocephalus in any of our tox studies.

Okay, okay. So the -- just thinking about -- I agree that there's a strong body of evidence that says that lowering wild-type Huntington seems to not be problematic. But there's a small study done in 2015 that shows that there's a transcription lowering variant, the lowest wild-type HTT, and that they actually correlated with an earlier disease onset of Huntington's. I'm sure you've seen this dataset. Just any thoughts around this? And just how does that play into your confidence that you're not going to see any negative effects of longer dosing, et cetera?

Yes. So you're referring to the [indiscernible] paper that was in Nature in 2015.

Yes.

Actually, the most important take-home point from that is the variant where they showed that the variant and the promoter that reduced expression of mutant Huntington, so lower mutant Huntington, delayed disease onset almost 10 years. That's actually the most compelling piece of data from that paper. In fact, they mentioned that the one that the variant that you mentioned in terms of potentially making the [ aged ones ] earlier, they could not validate that when they looked in other populations. So they even say that this is not validated. And -- but importantly, they were able to validate that reducing the mutant Huntington level is associated with a slowing of disease progression, at least a delay in the onset of the disease. And that's very, very important data.

Great. Just a quick question via email. Just any thoughts around the importance of targeting exon 1?

Yes. That's an interesting question. There has been some evidence that alternative exon 1 transcripts could be associated with juvenile Huntington disease. So that was a potential association in juvenile Huntington disease that has never been shown in adult Huntington disease. We have looked ourselves using RNA-seq at exon 1 average trends transcripts -- for everyone transcripts, we've not seen them in any of our preclinical studies and even in adult samples we've looked at.

Okay. Maybe we switch gears to 299. Could you give us an outline of this program? You're going to have data, I think, later this year. And so could you just describe what you've seen so far, great to gauge your level of enthusiasm here and what you're specifically looking for?

Yes. This is our COVID-19 program. So Emvododstat, which is also PTC299, its new name is Emvododstat is a DHODH inhibitor. And the reason that's so exciting and promising for COVID-19 is its dual mechanism of action. Through targeting DHODH, we're able to, one, affect viral replication by robbing the viral particles of essential building blocks by inhibiting DHODH, we're able to decrease viral replications so decrease viral load and also address the cytokine storm. So through target based activity of DHODH, we can decrease the production of the cytokines that underpin the systemic inflammatory and pulmonary inflammatory response, it's so important to COVID-19. So we have an oral molecule, very important because that can be used inpatient and outpatient. And with one oral molecule, we're able to affect both key pillars of COVID-19, the virus and the resulting cytokine storm. So we're now, as you mentioned, in a Phase II/III registration-directed study being conducted globally. That's moving forward very well. The primary endpoint of the study is the time to respiratory improvement as measured by sustained oxygen saturation equal to or greater than 94%. And this first I think is being done just in hospitalized patients, but obviously, we appreciate the benefit of the oral molecule that it can be also being used on an outpatient basis. And we recently -- we announced at earnings that we had completed part 1 of the 2-part registrational study and have now moved forward into Part 2 and enrollment's ongoing, and we look forward to sharing data later in 2021.

Fantastic. Maybe now one on AADC. So any update -- there's been some delays, any update on the progress with regards to the CHMP opinion and the BLA filing? I think one was due to delay with fusion inspection, so is that being rescheduled? And I think the other was due to some cannula surgery delays. And so could you walk us through that?

Yes, absolutely on it. Let's start with the CHMP side. So the CHMP asked us to request a clock stop so they can complete pre-approval inspections. They had actually started the inspections and these are mainly the GMP inspections. Now just for reference, all of our manufacturing sites are all down in the United States. Obviously, the CHMP is in the EU and travel and those types of things are not very easy. So they asked us for a delay clock stop to allow them to complete those inspections. So all that work is ongoing. And we look forward to an opinion, as we mentioned, by the end of the third quarter. On the BLA side, we've talked about in the past that one of the key gating factors for the BLA was the completion of surgical procedures using the commercial cannula. The cannula is that device that delivers the gene therapy directly into the right location in the brain. We're using a cannula that's commercialized by a company called ClearPoint Neuro. It's CE marked in the EU. So it's approved in the EU for gene therapy administration. It's 510 cleared in the U.S. for neurosurgical procedures but just not specifically to the administration of our gene therapy. So the agency said, look, we want you to do a bunch of benchtop testing showing that there's compatibility with your gene therapy product and the cannula. So we're sure what you put in is what you get out. You've done all that compatible. And then they wanted procedures done in the pediatric population, in which we're going to be commercializing the drug. And so we've done 2 of those procedures. The procedures went well, and we've been working towards getting that third one complete so that we can then move ahead and align with the agency and get the BLA on track.

Great. And in terms of the patient identification here, how are those activities progressing? In what settings are you identifying the most patients? Help us with that.

Yes. So this has been an effort we've been undertaking. We've said that we were targeting to identify 300 AADC patients at the time of launch, and we remain by that commitment. I think COVID has been a mixed bag. Obviously, some things got delayed during COVID. But at the same time, it was a great opportunity to introduce a number of our educational programs and master classes to increase awareness of the -- of AADC as well as to launch a number of our patient screening activities. We have a number of prospective and retrospective activities that are ongoing in high-risk populations. We have programs looking in cerebral palsy clinics as well as epilepsy clinics. Those are 2 places where AADC patients are often placed because they've been diagnosed. We have the genetic screening programs we introduced through our Pinpoint program and many others that we're conducting around the globe. And we're seeing really great progress during this time and expect to have continued pull-through from those efforts in our patient identification.

Fantastic. Maybe now let's switch to PTC923, it's a PKU. Just give us a quick overview of this program. We're initiating Phase III. So an overview, initiation time lines, enrollment readout, help us think through that.

Yes, absolutely. So we're really excited about the PTC923 program. In fact, we press release today that we have orphan designation in both the U.S. and EU. I think we all are well aware that despite there being a 2 approved therapies for PKU, there remains a large unmet medical need, really only a small proportion of the population being served by the existing therapies. PTC923 is a more bioavailable cofactor for phenylalanine hydroxylase, which is the enzyme that is defective in PKU. And we've been able to demonstrate in our Phase II study in a head-to-head comparison with Kuvan that we're able to achieve a much greater response. So we have 50% greater response rate with PTC923 as compared to Kuvan. And then when you look at the patients who showed a response to both Kuvan and PTC923, we had a greater than twofold reduction in phenylalanine levels in PTC923 patients relative to Kuvan. So really showing the benefits of PTC923. We also were able to demonstrate an effect in classical PKU patients that's that subgroup of PKU patients with the most severe disease, typically a baseline phenylalanine levels of over 1,200 micromolar per liter. So pretty severe, and we were able to demonstrate on average 170 micromolar per liter reduction in that most extreme population. So those are really, really nice data. So as we move forward into Phase III, we're in again, something we don't typically see in the rare neurological neuromuscular space, a clinical trial, which is -- where there's a precedent design that uses a blood-based biomarker for approval. So what we need to show is a reduction of phenylalanine levels. It's also a trial design that's been done before and adopted as acceptable by the regulatory agencies where we can actually enrich the population. We could actually screen patients by treating them with PTC923 for 2 weeks. And if they hit a target reduction in phenylalanine levels, we then enroll them to receive either PTC923 or placebo. So really the ultimate enrichment that placebo control phase will be 6 weeks. The primary endpoint as I mentioned will be reduction of phenylamine levels. We're going to be conducting this study globally. Really, what's also nice in PKU is there's an established organization of patients. There are expert centers. There's new board screening. So really all the trappings for a accelerated development program as well as accelerated commercial launch as a lot of the infrastructure is there already. We look forward to starting this study in mid-2021. We're on track to do that. We, again, are going to be deploying our global resources and leveraging our existing global development and commercial infrastructure to make sure that we can get enrollment as quickly as possible around flow. And we expect data, as we said, by year-end 2022.

Can you just say what the study is powered to show in terms of reduction?

We haven't given the exact numbers, but we have -- we're looking to have -- we've powered it around a reduction of 30% of phenylalanine levels. So we're able to actually -- we're able to enrich the population that is in the primary analysis group for those who we know are going to have a reduction of 30%.

Right, right.

When you look at those numbers, it's about 80 subjects that we would need to have be overpowered. We anticipate that we'll screen more than that, obviously, to get to those target 80, but we'll also treat all patients responders or not and have those helped build out the study database.

Great. Maybe now let's talk about the Bio-e platform. You touched upon it in your prepared remarks. Can you start broadly and just talk about what the genesis of this platform? And then we can dig into some of the more specifics, the vatiquinone, et cetera?

Yes, absolutely. So the Bio-e platform is basically built around a family of enzymes known as oxidoreductase enzymes. These are a special group of enzymes long known to be important in the regulation of energy generation inflammation and oxidative stress. These enzymes are governors of a number of important inflammation oxidative stress pathways, and they've been implicated in a number of diseases. However, previously, they've resisted systematic drugging because to turn these enzymes on and off, not only do you need a lock in key effect like you usually think about when you have a drug in an enzyme. But these enzymes are special in that in order to turn them on and off, you have to move in electron. So you have to get the key in the lock, but then transfer an electron to flip a switch on these enzymes either on and off. Okay? So what we have in the Bio-e platform is these enzymes that are important and a library of redox-active compounds. That is compounds that can talk that unique electron language. We can drug these targets with these compounds, get the lock in key and fine-tune their electrochemical properties, something we don't talk a lot about, to allow them to effectively turn it off these enzymes. So really, really exciting. The first target we've been focused on is the enzyme 15-lipoxygenase. 15-lipoxygenase is a well-recognized regulator of an inflammation of oxidative stress just pathway. More recently, people referring to as ferroptosis. It's been shown to be very important in a number of neurological disease in our degenerative disorders as well as in epilepsy syndromes. And we've been undergoing efforts with particularly on our lead compound for targeting 15-lipoxygenase for pediatric mitochondrial disease, specifically our registration-directed trial in refractory mitochondrial epilepsy and Friedreich ataxia disease where iron oxidative stress inflation 15-lipoxygenase have all been shown to be key to that disease pathology.

And so for the mitochondria efficacy and the Friedreich ataxia, can you just -- can you give us a little more information on the trial designs and then the time lines we're working on? And ultimately, what you need -- you think you need to show to satisfy regulators.

Yes, absolutely. So the mitochondrial epilepsies trial refers to the symptom of refractory seizures in children with genetically confirmed mitochondrial disease. About half of all patients with mitochondrial disease have seizures as a part of their disease. And the vast majority of these seizures don't respond to typical antiepileptic therapies. The reason for that is typical antiepileptic therapies don't target those energetic oxidative stress pathways that underpin seizures in these patients. Actually, many antiepileptic therapies actually increase oxidative stress. So any benefit you're getting is offset by an exacerbation of the pathology of the disease. We've obviously done a lot of preclinical work based on the mechanism of action of vatiquinone in a number of different models showing an effect in protecting patient cells. We've also done a clinical work in a number of different studies. We've been able to show in different mitochondrial disease subtypes, the ability to affect seizure frequency, disrupt refractory status epilepticus prevented from occurring. And in one highly morbid subgroup, we've also been able to show a reduction in hospital related -- I mean in disease-related hospitalizations as well as a reduction in mortality risk. So we use all of those data as the foundation for this Phase II/III trial. We're enrolling approximately 60 subjects globally. We're tapping into our global network in mitochondrial disease that's been well-established over a number of years. A study design that's very similar to what's been used in other pediatric epilepsy syndromes. We have a month run-in where all subjects have to demonstrate a minimum number of observable motor seizures. Those that meet that criteria will then get randomized to receive either vatiquinone or placebo for 6 months. That's a little longer than it's usually done. And the reason for that is we want to make sure we capture some of those other important impacts on disease morbidity beyond just seizure reduction. And then after the data readout or after the completion of the placebo controlled phase, also this will participate in a long-term open-label extension. This is a study that was actually designed in collaboration with the regulatory authorities. In fact, we had one regulatory agency that are -- there was a lot of pull for us to do this study. They wanted us to do this basket study given the high unmet medical need in the mitochondrial disease population. And we set as the primary endpoint, as I mentioned, a reduction in observable motor seizures. And we are targeting a reduction on average of 50% in the treatment group, which is usually a clear threshold that would allow for approval. And then we're also capturing a number of secondary endpoints around seizure burden, rescue medications and other aspects of disease morbidity. The study kicked off enrollment towards the end of last year. It was really a conscious decision we made and despite the fragility of these children, we still decided to start the trial and amidst of a COVID pandemic, we did so with eyes wide open, but we did several important things to enhance the [ successive ] enrollment. We included a number of additional study sites. We have geographic diversity of expert centers so that travel distance can be minimized. We've also included aspects to the protocol which could be done remotely with a primary endpoint of observable seizures to an electronic seizure diary. The primary endpoints collected through web-based application at home. And so this was something that we were able to do to again reduce concerns that families would have taken highly from children out in a COVID environment. So enrollments ongoing, going well, and we expect to have data in the third quarter of 2022.

Great. That's fantastic. Maybe turning to the commercial side of the business. In 1Q, we saw an uptick in Emflaza sales. Could you just talk about the underlying drivers of this? And should we expect them to stay and this to be the new cadence throughout the rest of the year?

Let me kick that over to Eric to handle that.

Thanks, Matt. And Colin, we're very excited that -- I'm really pleased that overall with the DMD growth. We saw one of our strongest quarterly revenues to date. And that was led through incredible growth, not just from Translarna, but Emflaza was really leading the way at 58% growth compared to Q1 of last year. I just want to remind you that Emflaza is the first and only FDA-approved treatment for all DMD patients 2 years and older. So we're actually able to address the largest amount of DMD patients irrespective of genotype. So right now, we have accumulated one of the largest databases of patients on treatment. That growth it has really not come from a lot of various things. Of course, our teams have been executing at an exceptionally high level, even during the COVID pandemic. We're seeing continued new patient starts month-on-month. So that's really encouraging. We've also been able to reduce what we call patient assistance and bridge programs which is essentially free drug. And we've been able to reduce the time that patients actually get free drug and move them quickly to commercial. And a lot of that has to do with our market access teams that have reduced many of the restrictions around early prednisone usage or step edits. We've also been able to maintain very high levels of compliance. Now for any drug, people would be -- have the oral drugs, we'd be happy at 70%, 80%. We've had been maintaining compliance levels, well over 90%, and that's extremely important and has contributed. And at the same time, we've also lowered the amount of treatment discontinuations. So when you have a large base of patients that are currently on drug and, of course, in a rare disease like this, part of your role is not only to get new patients but also maintain that large base of patients and minimize discontinuations. Now a lot of this has been motivated, not just because of the execution and market dynamics but it's really been coupled with a number of key things. We've had really a mountain of data that has shown how Emflaza is really differentiated versus prednisone. And recently, we've had new data presented, it's Emflaza real-world switch data, where patients and caregivers and physicians have switched from prednisone to Emflaza, and we presented that data MDA at AAN. And we continue to see and hear back from families and physicians, the product is really clinically differentiated over prednisone. So in essence, we're seeing good, strong execution and a lot of really good clinical data that's helping us in the real world, differentiate the product. And I think we've got some really good tailwinds right now. As we went through in the first quarter, we're seeing continued growth, and we would expect that in 2021 and beyond.

Okay. Great. That's really helpful. Maybe on Translarna, could you just give us a refresher of just where we are from that? What data have you shown? Where we are in terms of the path to refiling? And just -- and the time line that surround that.

Sure. I'll take that, Colin. So as we had talked about, when we shared our dystrophin data, we, of course, we're happy to be able to report that the majority of boys treated with Translarna demonstrated an increase in dystrophin expression following treatment. Importantly, we also observed that in 8 of the 20 boys who had a delay in their final study biopsy due to COVID, they just simply couldn't get to the study site for their biopsies. We saw an even larger increase in dystrophin production, which is really compelling evidence that long-term therapy with Translarna has biological as well as the important clinical benefits we've been able to observe. This puts Translarna in a very interesting place because now you have biochemical evidence effect. And also, we have several pieces of clinical evidence of beneficial effect, including the pooled analyses from our earlier placebo-controlled studies and our STRIDE registry with real-world data that shows over the course of years, there's an important Translarna benefit. Specifically, we've been able to show a delay in loss of ambulation, a delay in loss of pulmonary function, really 2 of the key morbid events in the course of Duchenne muscular dystrophy. So to be able to have a totality of data, including long-term evidence of benefit in relation to the key morbid aspects of disease, it makes an incredibly compelling package. We're still in the process of completing some analyses, including some of the more recent data we harvested from the real world study in terms of whether that would be part of a totality of evidence discussion for an accelerated approval now. But either way, we're moving full steam ahead with completion of what we call our study [ hope for one ] which is a global placebo-controlled trial that was part of our conditional marketing authorization in Europe. So that's being done as a global study. And that placebo-controlled study, which is going to readout in Q3 of 2022 can absolutely stand as the key approval trial in the United States. That trial incorporates a lot of the key learnings we've made over the years in developing Translarna for Duchenne muscular dystrophy, including the duration of the placebo controlled phase, which is now 72 weeks. We believe that's really appropriate length to capture that benefit relative to the decline in placebo population and as well as an intent-to-treat population that is really where we believe is the sweet spot. We've seen our data as a sweet spot for demonstrating Translarna effect with regard to baseline 6-minute walk test parameters. So we are, again, full speed ahead in that trial. I look forward to the data in Q3 2022. And that positive trial would certainly be the -- would support approval in -- or be able to support the NDA for approval in the United States.

Okay. That's great. And maybe just on the commercial side, again, just switching to risdiplam. Just anything you feel is underappreciated in terms of the drivers and just refresh us on your expectations for the rest of the year.

I'll kick that back over to Eric.

Well, I'll probably kick it over to Kylie, too. She is here. So I think she can probably handle this one here.

Absolutely. Thanks, Eric, and thanks for the question, Colin. Yes. So we've been, I think, very impressed with the initial uptake in the U.S. We've seen 1,600 U.S. patients treated in quite a rapid time, so roughly 8 months after launch. And that represents more than 15% market share in such a short period of time. And so we've seen the composition of patients treated across all SMA types with the patent mirroring disease prevalence. So roughly 25% of patients in Type 1, 50% Type 2 and 25% Type 3. From a naive as previously treated perspective, roughly 1/3 of the patients have been treatment naive. And 2/3 being previously treated by both SPINRAZA and Zolgensma. And we're seeing that we've had some strong uptake with market access and payer engagement with more than 75% of lives being covered already in that early 8 month period. So again, with the age range 2 months old to more than 70-plus years adults. So across all SMA types across patient naive -- treatment naive, sorry, and previously treated and a broad ranges really showing the unmet medical need that existed in SMA. And as Matt mentioned in some of the opening remarks, we've seen EMA approval recently, and we saw the first EU sale the following day. And this really in my opinion, clearly highlights the pent-up need in Europe and the remaining unmet medical need. And so we do expect the initial uptake in the growth that we're seeing in the U.S. to also exist in Europe, and we do expect growth over the coming quarters within Europe. And then in addition to that, we do expect the Japanese approval before the end of 2021 and expect the ex U.S. growth to continue.

Great. Thank you. We're getting to the end of time. We've covered a lot, but you guys have a lot going on. Maybe I just turn over to 3 you and just is there anything we haven't covered that really getting a lot of questions on or that you're particularly enthused about that you want to shine lights on?

Yes. I think from my side and for all of us, I'll like Kylie maybe chime in as well. I think we're incredibly excited about all the activities we have ongoing. As you mentioned, we have the registration-directed trials to the Bio-e platform, mitochondrial epilepsy and Friedreich ataxia, which are ongoing with a 923 registration-directed trial, COVID-19 registration-directed trial, the advance of AEC, MAA and soon BLA, all incredibly exciting activities as well as the continued commercial growth and excellence.

Great. Anymore?

Yes. I think just in addition to that, I think we have some near-term value drivers that I think we're looking forward to really shifting towards commercialization and being able to demonstrate our strong commercial infrastructure that we have built across a number of different geographies that we're utilizing for both Translarna and, of course, Emflaza and down in LatAm as well. And so we're looking forward to bringing those to market and being able to really utilize that commercial infrastructure.

Yes. And I'd also just add that a part of what we're doing is not only leveraging commercial infrastructure, but we're also expanding geographically in Central and Eastern Europe, we've launched in Russia. You had now coverage for Translarna in Russia. And we're opening up our offices in the second half, and we're building out our Japanese presence, which is very important in terms of managing some of the products that will be coming down the pipeline, well suited for the Japanese market and reinforcing our geographic position in Latin America. So part of what we're going to continue to do is not only invest in the pipeline invest in our current infrastructure, but also expand geographically, which is a natural consequence of finding patients where access and reimbursement exists.

That's great. I think we are certainly at end of time now. So this has been a fantastic presentation. Thank you to all of you. Thank you to everyone who's dialed in. If anyone has any follow-up, feel free to e-mail me [email protected]. And with that, thanks again, and have a great day.

Thank you.

Thank you.

Thanks, Colin, for having us.

Thanks, Colin.